med 11

El-Shattawy HH, Peck GE, Kildsig DO. Aspartame direct compression excipients: preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7(5):

605–619.

El-Shattaway HH. Ampicillin direct compression excipients: preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 819–831.

El-Shattaway HH, Kildsig DO, Peck GE. Cephalexin I direct compression excipients: preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6):

897–909.

El-Shattaway HH, Kildsig DO, Peck GE. Erythromycin direct compression excipients: preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6):

937–947.

General References

Green CE, Makhija RG, Carstensen JT. R-P trials calcium excipient.

Manuf Chem 1996; 67(8): 55, 57.

Rhodia. Technical literature: Calcium phosphate excipients, 1999.

Calcium Phosphate, Tribasic

Nonproprietary Names

BP: Calcium phosphate PhEur: Tricalcii phosphas

USPNF: Tribasic calcium phosphate

Synonyms

Calcium orthophosphate; E341; hydroxylapatite; phosphoric acid calcium salt (2 : 3); precipitated calcium phosphate; tertiary calcium phosphate; Tri-Cafos; tricalcium diortho- phosphate; tricalcium orthophosphate; tricalcium phosphate; TRI-CAL WG; TRI-TAB.

Chemical Name and CAS Registry Number

Tribasic calcium phosphate is not a clearly defined chemical entity but is a mixture of calcium phosphates. Several chemical names, CAS Registry Numbers, and molecular formulas have therefore been used to describe this material. Those most frequently cited are shown below.

Calcium hydroxide phosphate [12167-74-7] Tricalcium orthophosphate [7758-87-4]

See also Sections 4 and 8.

Empirical Formula and Molecular Weight

Ca3(PO4)2 310.20

Ca5(OH)(PO4)3 502.32

Structural Formula

See Sections 3 and 4.

Functional Category

Anticaking agent; buffer; dietary supplement; glidant; tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Tribasic calcium phosphate is widely used as a capsule diluent and tablet filler/binder in either direct-compression or wet- granulation processes. The primary bonding mechanism in compaction is plastic deformation. As with dibasic calcium phosphate, a lubricant and a disintegrant should usually be incorporated in capsule or tablet formulations that include tribasic calcium phosphate. In some cases tribasic calcium phosphate has been used as a disintegrant.(1) It is most widely used in vitamin and mineral preparations(2) as a filler and as a binder. It is a source of both calcium and phosphorus, the two main osteogenic minerals for bone health. The bioavailability of the calcium is well known to be improved by the presence of cholecalciferol. Recent research reports that combinations of tribasic calcium phosphate and vitamin D3 are a cost-effective advance in bone fracture prevention.(3)

In food applications, tribasic calcium phosphate powder is widely used as an anticaking agent. See Section 18.

See also Calcium phosphate, dibasic dihydrate.

Description

The PhEur 2005 states that tribasic calcium phosphate consists of a mixture of calcium phosphates. It contains not less than 35.0% and not more than the equivalent of 40.0% of calcium. The USPNF 23 specifies that tribasic calcium phosphate consists of variable mixtures of calcium phosphates having the approximate composition 10CaO·3P2O5·H2O. This corre- sponds to a molecular formula of Ca5(OH)(PO4)3 or Ca10(OH)2(PO4)6.

Tribasic calcium phosphate is a white, odorless and tasteless powder.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for tribasic calcium phosphate.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Loss on ignition 48.0% 48.0%

Water-soluble substances — 40.5%

Acid-insoluble substances 40.2% 40.2%

Carbonate — +

Chloride 40.15% 40.14%

Fluoride 475 ppm 40.0075%

Nitrate — +

Sulfate 40.5% 40.8%

Arsenic 44 ppm 43 ppm

Barium — +

Iron 4400 ppm —

Dibasic salt and calcium oxide — +

Heavy metals 430 ppm 40.003%

Assay (as Ca) 35.0–40.0% 34.0–40.0%

Typical Properties

Acidity/alkalinity: pH = 6.8 (20% slurry in water)

Density: 3.14 g/cm3

Density (bulk):

0.3–0.4 g/cm3 for powder form;

0.80 g/cm3 for granular TRI-TAB.(4)

Density (tapped): 0.95 g/cm3 for granular TRI-TAB.(4)

Flowability: 25.0 g/s for granular TRI-TAB(4)

Melting point: 16708C

Moisture content: slightly hygroscopic. A well-defined crystal- line hydrate is not formed although surface moisture may be picked up or contained within small pores in the crystal structure. At relative humidities between about 15% and 65%, the equilibrium moisture content at 258C is about 2.0%. At relative humidities above about 75%, tribasic calcium phosphate may absorb small amounts of moisture. Particle size distribution: Tribasic calcium phosphate powder:

typical particle diameter 5–10 mm; 98% of particles <44 mm. TRI-CALWG: average particle diameter 180 mm; 99% of particles <420 mm, 46% <149 mm, and 15% <44 mm in size.

Calcium Phosphate, Tribasic 101

TRI-TAB: average particle diameter 350 mm; 97% of particles <420 mm, and 2% <149 mm.

Solubility: soluble in dilute mineral acids; very slightly soluble

in water; practically insoluble in acetic acid and alcohols.

Specific surface area: 70–80 m2/g(4)

Stability and Storage Conditions

Tribasic calcium phosphate is a chemically stable material, and is also not liable to cake during storage.

The bulk material should be stored in a well-closed container in a cool, dry place.

Incompatibilities

All calcium salts are incompatible with tetracycline antibiotics. Tribasic calcium phosphate is incompatible with tocopheryl acetate (but not tocopheryl succinate). Tribasic calcium phosphate may form sparingly soluble phosphates with hormones.

Method of Manufacture

Tribasic calcium phosphate occurs naturally as the minerals hydroxylapatite, voelicherite, and whitlockite. Commercially, it is prepared by treating phosphate-containing rock with sulfuric acid. Tribasic calcium phosphate powder is then precipitated by the addition of calcium hydroxide. Tribasic calcium phosphate is alternatively prepared by treating calcium hydroxide from limestone with purified phosphoric acid. It may also be obtained from calcined animal bones.(5) Some tribasic calcium phosphate products may be prepared in coarser, directly compressible forms by granulating the powder using roller compaction or spray drying.

Safety

Tribasic calcium phosphate is widely used in oral pharmaceu- tical formulations and food products and is generally regarded as nontoxic and nonirritant at the levels employed as a pharmaceutical excipient.

Ingestion or inhalation of excessive quantities may result in the deposition of tribasic calcium phosphate crystals in tissues. These crystals may lead to inflammation and cause tissue lesions in the areas of deposition.

Oral ingestion of very large quantities of tribasic calcium phosphate may cause abdominal discomfort such as nausea and vomiting.

No teratogenic effects were found in chicken embryos exposed to a dose of 2.5 mg of tribasic calcium phosphate.(6)

LD50 (rat, oral): >1 g/kg(4)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Handle in a well-ventilated environment since dust inhalation may be an irritant. For processes generating large amounts of dust, the use of a respirator is recommended.

Regulatory Acceptance

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Calcium phosphate, dibasic anhydrous; calcium phosphate, dibasic dihydrate.

Comments

One gram of tribasic calcium phosphate represents approxi- mately 10.9 mmol of calcium and 6.4 mmol of phosphate; 38% calcium and 17.3% phosphorus by weight.(4) Tribasic calcium phosphate provides a higher calcium load than dibasic calcium phosphate and a higher Ca/P ratio. Granular and fine powder forms of tribasic calcium phosphate are available from various manufacturers.

A specification for calcium phosphate tribasic is contained in the Food Chemicals Codex (FCC).

The EINECS number for calcium phosphate is 231-837-1.

Specific References

Delonca H, Puech A, Segura G, Youakim J. Effect of excipients and storage conditions on drug stability I: acetylsalicylic acid-based tablets [in French]. J Pharm Belg 1969; 24: 243–252.

Magid L. Stable multivitamin tablets containing tricalcium phosphate. United States Patent No. 3,564,097; 1971.

Lilliu H, Chapuy MC, Meunier PJ, et al. Calcium-vitamin D3 supplementation is cost-effective in hip fractures prevention. Muturitas 2003; 44(4): 299–305.

Rhodia. Technical literature: Calcium phosphate pharmaceutical ingredients, 1995.

Magami A. Basic pentacalcium triphosphate production. Japanese Patent 56 022 614; 1981.

Verrett MJ, Scott WF, Reynaldo EF, et al. Toxicity and teratogenicity of food additive chemicals in the developing chicken embryo. Toxicol Appl Pharmacol 1980; 56: 265–273.

General References

Bryan JW, McCallister JD. Matrix forming capabilities of three calcium diluents. Drug Dev Ind Pharm 1992; 18: 2029–2047.

Chowhan ZT, Amaro AA. The effect of low- and high-humidity aging on the hardness, disintegration time and dissolution rate of tribasic calcium phosphate-based tablets. Drug Dev Ind Pharm 1979; 5: 545–562.

Fischer E. Calcium phosphate as a pharmaceutical excipient. Manuf Chem 1992; 64(6): 25–27.

Kutty TRN. Thermal decomposition of hydroxylapatite. Indian J Chem 1973; 11: 695–697.

Molokhia AM, Moustafa MA, Gouda MW. Effect of storage conditions on the hardness, disintegration and drug release from some tablet bases. Drug Dev Ind Pharm 1982; 8: 283–292.

Pontier C, Viana M. Energetic yields in apatitic calcium phosphate compression: influence of the Ca/P molar ratio. Polymer Interna- tional 2003; 52(4): 625–628.

Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting 1: physico-pharmaceutical properties. Pharm World Sci 1993; 15(3): 105–115.

Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting 2: comparison of tableting properties. Pharm World Sci 1993; 15(3): 116–122.

Authors

V King, L Hendricks, W Camarco.

BP: Calcium stearate JP: Calcium stearate PhEur: Calcii stearas

USPNF: Calcium stearate

Synonyms

Calcium distearate; HyQual; stearic acid, calcium salt; calcium octadecanoate; octadecanoic acid, calcium salt.

Chemical Name and CAS Registry Number

Octadecanoic acid calcium salt [1592-23-0]

Empirical Formula and Molecular Weight

C36H70CaO4 607.03 (for pure material)

The PhEur 2005 describes calcium stearate as a mixture of calcium salts of different fatty acids consisting mainly of stearic acid [(C17H35COO)2Ca] and palmitic acid [(C15H31COO)2Ca] with minor proportions of other fatty acids. It contains the equivalent of 9.0–10.5% of calcium oxide.

Structural Formula

Functional Category

Tablet and capsule lubricant.

Applications in Pharmaceutical Formulation or Technology

Calcium stearate is primarily used in pharmaceutical formula- tions as a lubricant in tablet and capsule manufacture at concentrations up to 1.0% w/w. Although it has good antiadherent and lubricant properties, calcium stearate has poor glidant properties.

Calcium stearate is also employed as an emulsifier, stabiliz- ing agent, and suspending agent, and is also used in cosmetics and food products.

Description

Calcium stearate occurs as a fine, white to yellowish-white, bulky powder having a slight, characteristic odor. It is unctuous and free from grittiness.

SEM: 1

Excipient: Calcium stearate (Standard)

Manufacturer: Durham Chemicals

Lot No.: 0364

Voltage: 20 kV

SEM: 2

Excipient: Calcium stearate (Precipitated)

Manufacturer: Witco Corporation

Excipient: Calcium stearate (Fused) Manufacturer: Witco Corporation Voltage: 15 kV

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for calcium stearate.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters + + —

Microbial limit — 103/g —

Acidity or alkalinity — + —

Loss on drying 44.0% 46.0% 44.0%

Arsenic 42 ppm — —

Heavy metals 420 ppm — 410 mg/g

Organic volatile impurities — — +

Assay (as CaO) — — 9.0–10.5%

Assay (as Ca) 6.4–7.1% 6.4–7.4% —

Density (bulk and tapped): see Table II.

Density (true): 1.064–1.096 g/cm3

Flowability: 21.2–22.6% (Carr compressibility index)

Free fatty acid: 0.3–0.5% Melting point: 149–1608C Moisture content: 2.96%

Particle size distribution: 1.7–60 mm; 100% through a 73.7 mm (#200 mesh); 99.5% through a 44.5 mm (#325 mesh).

Table II: Density (bulk and tapped) of calcium stearate.

Bulk density (g/cm3) Tapped density (g/cm3)

Precipitated 0.16 0.20

Shear strength: 14.71 MPa

Solubility: practically insoluble or insoluble in ethanol (95%), ether, chloroform, acetone and water. Slightly soluble in hot alcohol, and hot vegetable and mineral oils. Soluble in hot pyridine.

Specific surface area: 4.73–8.03 m2/g

Sulfate: <0.25%

Stability and Storage Conditions

Calcium stearate is stable and should be stored in a well-closed container in a cool, dry place.

Incompatibilities

—

Method of Manufacture

Calcium stearate is prepared by the reaction of calcium chloride with a mixture of the sodium salts of stearic and palmitic acids. The calcium stearate formed is collected and washed with water to remove any sodium chloride.

Safety

Calcium stearate is used in oral pharmaceutical formulations and is generally regarded as a relatively nontoxic and nonirritant material.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Calcium stearate should be used in a well-ventilated environment; eye protection, gloves, and a respirator are recommended.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Magnesium stearate; stearic acid; zinc stearate.

Comments

Calcium stearate exhibits interesting properties when heated; softening between 120–1308C, and exhibiting a viscous

104 Calcium Stearate

consistency at approximately 1608C. At approximately 1008C, it loses about 3% of its weight, corresponding to one mole of water of crystallization. The crystalline structure changes at this point, leading to the collapse of the crystal lattice at a temperature of about 1258C.(1)

See Magnesium stearate for further information and references.

A specification for calcium stearate is contained in the Food Chemicals Codex (FCC).

The EINECS number for calcium stearate is 216-472-8.

Specific References

1 SpecialChem (2005). Metallic stearates center. http://www.specialchem4polymers.com/tc/metallic-stearates/ index.aspx?id-2404 (accessed 9 August 2005).

General References

Bu¨ sch G, Neuwald F. Metallic soaps as water-in-oil emulsifiers [in German]. J Soc Cosmet Chem 1973; 24: 763–769.

Phadke DS, Sack MJ. Evaluation of batch-to-batch and manufacturer- to-manufacturer variability in the physical and lubricant properties of calcium stearate. Pharm Technol 1996; 20(Mar): 126–140.

BP: Calcium sulphate dihydrate PhEur: Calcii sulfas dihydricus USPNF: Calcium sulfate

Synonyms

Calcium sulfate anhydrous: anhydrite; anhydrous gypsum; anhydrous sulfate of lime; Destab; Drierite; E516; karste- nite; muriacite; Snow White.

Calcium sulfate dihydrate: alabaster; Cal-Tab; Compactrol; Destab; E516; gypsum; light spar; mineral white; native calcium sulfate; precipitated calcium sulfate; satinite; satin spar; selenite; terra alba; USG Terra Alba.

Chemical Name and CAS Registry Number

Calcium sulfate [7778-18-9]

Calcium sulfate dihydrate [10101-41-4]

Empirical Formula and Molecular Weight

Tablet and capsule diluent. The anhydrous form is used as a desiccant.

Applications in Pharmaceutical Formulation or Technology

Calcium sulfate dihydrate is used in the formulation of tablets and capsules. In granular form it has good compaction properties and moderate disintegration properties.(1,2)

Calcium sulfate hemihydrate (see Section 17), is used in the preparation of plaster of Paris bandage, which is used for the immobilization of limbs and fractures; it should not be used in the formulation of tablets or capsules.

Anhydrous calcium sulfate is hygroscopic and uptake of water can cause the tablets to become very hard and to fail to disintegrate on storage. It is not recommended for the formulation of tablets, capsules, or powders for oral adminis- tration.

Therapeutically, calcium sulfate is used in dental and craniofacial surgical procedures.(3,4)

Description

A white or off-white, fine, odorless, and tasteless powder or granules.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for calcium sulfate.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Acidity or alkalinity + —

Arsenic 410 ppm —

Chlorides 4300 ppm —

Heavy metals 420 ppm 40.001%

Iron

Loss on drying 4100 ppm 40.01%

Anhydrous — 41.5%

Dihydrate — 19.0–23.0%

Loss on ignition 18.0–22.0% —

Assay 98.0–102.0% 98.0–101.0%

Typical properties

Acidity/alkalinity:

pH = 7.3 (10% slurry) for dihydrate;

pH = 10.4 (10% slurry) for anhydrous material.

Angle of repose: 37.68 for Compactrol.(2)

Compressibility: see Figure 1.

Figure 1: Compression characteristics of calcium sulfate dihydrate.

Tablet weight: 700 mg.

106 Calcium Sulfate

Density (bulk):

0.94 g/cm3 for Compactrol;(2)

0.67 g/cm3 for dihydrate;

0.70 g/cm3 for anhydrous material.

Density (tapped):

1.10 g/cm3 for Compactrol;(2)

1.12 g/cm3 for dihydrate;

1.28 g/cm3 for anhydrous material.

Density (true): 2.308 g/cm3

Flowability: 48.4% (Carr compressibility index); 5.2 g/s for

Compactrol.(2)

Melting point: 14508C for anhydrous material.

Particle size distribution: 93% less than 45 mm in size for the dihydrate (USG Terra Alba); 97% less than 45 mm in size for the anhydrous material (Snow White). Average particle size is 17 mm for the dihydrate and 8 mm for the anhydrous material. For Compactrol, not less than 98% passes through a #40 screen (425 mm), and not less than 85% is retained in a #140 screen (100 mm).

Solubility: see Table II.

Table II: Solubility of calcium sulfate dihydrate.

Solvent Solubility at 208C unless otherwise stated

Ethanol (95%) Practically insoluble Water 1 in 375

1 in 485 at 1008C

Specific gravity:

2.32 for dihydrate;

2.96 for anhydrous material.

Specific surface area: 3.15 m2/g (Strohlein apparatus)

Stability and Storage Conditions

Calcium sulfate is chemically stable. Anhydrous calcium sulfate is hygroscopic and may cake on storage. Store in a well-closed container in a dry place, avoiding heat.

Incompatibilities

In the presence of moisture, calcium salts may be incompatible with amines, amino acids, peptides, and proteins, which may form complexes. Calcium salts will interfere with the bioavail- ability of tetracycline antibiotics.(5) It is also anticipated that calcium sulfate would be incompatible with indomethacin,(6) aspirin,(7) aspartame,(8) ampicillin,(9) cephalexin,(10) and eryth- romycin(11) since these materials are incompatible with other calcium salts.

Calcium sulfate may react violently, at high temperatures, with phosphorus and aluminum powder; it can react violently with diazomethane.

Method of Manufacture

Anhydrous calcium sulfate occurs naturally as the mineral anhydrite. The naturally occurring rock gypsum may be crushed and ground for use as the dihydrate or calcined at 1508C to produce the hemihydrate. A purer variety of calcium sulfate may also be obtained chemically by reacting calcium carbonate with sulfuric acid or by precipitation from calcium chloride and a soluble sulfate.

Safety

Calcium sulfate dihydrate is used as an excipient in oral capsule and tablet formulations. At the levels at which it is used as an excipient, it is generally regarded as nontoxic. However, ingestion of a sufficiently large quantity can result in obstruc- tion of the upper intestinal tract after absorption of moisture.

Owing to the limited intestinal absorption of calcium from its salts, hypercalcemia cannot be induced even after the ingestion of massive oral doses.

Calcium salts are soluble in bronchial fluid. Pure salts do not induce pneumoconiosis.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. The fine-milled grades can generate nuisance dusts that may be irritant to the eyes or on inhalation. The use of a respirator or dust mask is recom- mended to prevent excessive powder inhalation since excessive inhalation may saturate the bronchial fluid, leading to precipitation and thus blockage of the air passages.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral capsules, sustained release, tablets). Included in nonparenteral medicines licensed in the UK and Europe. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Calcium phosphate, dibasic anhydrous; calcium phosphate, dibasic dihydrate; calcium phosphate, tribasic; calcium sulfate hemihydrate.

Calcium sulfate hemihydrate Empirical formula: CaSO4·1/2H2O Molecular weight: 145.14

CAS number: [26499-65-0]

Synonyms: annalin; calcii sulfas hemihydricus; calcined gyp- sum; dried calcium sulfate; dried gypsum; E516; exsiccated calcium sulfate; plaster of Paris; sulfate of lime; yeso blanco. Appearance: a white or almost white, odorless, crystalline,

hygroscopic powder.

Solubility: practically insoluble in ethanol (95%); slightly soluble in water; more soluble in dilute mineral acids.

Comments: the BP 2004 defines dried calcium sulfate as predominantly the hemihydrate, produced by drying pow- dered gypsum (CaSO4·2H2O) at about 1508C, in a controlled manner, such that minimum quantities of the anhydrous material are produced. Dried calcium sulfate may also contain suitable setting accelerators or decelera- tors.

Comments

Calcium sulfate will absorb moisture and therefore should be used with caution in the formulation of products containing drugs that easily decompose in the presence of moisture. A specification for calcium sulfate is contained in the Food Chemicals Codex (FCC). The EINECS number for calcium sulfate is 231-900-3.

Calcium Sulfate 107

Specific References

Bergman LA, Bandelin FJ. Effects of concentration, ageing and temperature on tablet disintegrants in a soluble direct compression system. J Pharm Sci 1965; 54: 445–447.

C¸ elik M, Okutgen E. A feasibility study for the development of a prospective compaction functionality test and the establishment of a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309– 2334.

Cho BC, Park JW, Baik BS, Kim IS. Clinical application of injectable calcium sulfate on early bone consolidation in distrac- tion osteogenesis for the treatment of craniofacial microsomia. J Craniofac Surg 2002; 13(3): 465–474.

Deporter DA, Todescan R. A possible ‘rescue’ procedure for dental implants with a textured surface geometry: a case report. J Periodontol 2001; 72(10): 1420–1423.

Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation Agents: A Handbook of Excipients. New York: Marcel Dekker, 1989: 93–94.

Eerika¨ inen S, Yliruusi J, Laakso R. The behaviour of the sodium salt of indomethacin in the cores of film-coated granules contain- ing various fillers. Int J Pharm 1991; 71: 201–211.

Land´ın M, Pe´rez-Marcos B, Casalderrey M, et al. Chemical stability of acetylsalicylic acid in tablets prepared with different commercial brands of dicalcium phosphate dihydrate. Int J Pharm 1994; 107: 247–249.

El-Shattawy HH, Peck GE, Kildsig DO. Aspartame – direct compression excipients: preformulation stability screening using

differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7(5):

605–619.

El-Shattawy HH. Ampicillin – direct compression excipients: preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 819–831.

El-Shattawy HH, Kildsig DO, Peck GE. Cephalexin 1 – direct compression excipients: preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6):

897–909.

El-Shattawy HH, Kildsig DO, Peck GE. Erythromycin – direct compression excipients: preformulation stability screening using differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6):

937–947.

General References

Bryan JW, McCallister JD. Matrix forming capabilities of three calcium diluents. Drug Dev Ind Pharm 1992; 18: 2029–2047.

Canbra oil; Colzao CT; Lipex 108; Lipex 204; Lipovol CAN; low erucic acid colza oil; low erucic acid rapeseed oil.

Chemical Name and CAS Registry Number

Canola oil [120962-03-0]

Empirical Formula and Molecular Weight

Canola oil contains approximately 6% saturated acids, 2% monounsaturated acids, and 32% polyunsaturated acids; see Table I. Additionally, sulfur-containing fatty acids may also be present as minor constituents.

Table I: Typical composition of glycerides present in canola oil.

Glyceride Amount present (%)

Erucic acid 0.2–1.8

Palmitic acid 3.0–4.5

Palmitoleic acid 0.2–0.3

Stearic acid 1.3–1.7

Linoleic acid 19.0–24.0

Oleic acid 56.0–62.0

The sulfur-containing compounds have been held respon- sible for the unpleasant odors from heated rapeseed oil. It has been suggested that the sulfur compounds in rapeseed oil are of three types: volatile, thermolabile, and nonvolatile.(1)

Unrefined canola oil is said to contain low levels of sulfur- containing fatty acids, resulting in the presence of sulfur in the oil in the stable form of triglycerides. These triglycerides resist refining procedures.(2) See Table II for the sulfur content of crude, refined, and deodorized canola oils.(3)

Table II: Total sulfur content in crude, refined and bleached and deodorized canola oil.(a)

Oil sample Range (mg/kg) Mean Standard deviation

Crude 23.6–24.1 23.8 1.0

Refined 19.1–20.2 19.7 2.85

Bleached and deodorized 15.6–16.5 16.2 2.7

(a) Determined using five replicates of each sample analyzed by ion chromatography.

Structural Formula

See Section 4.

Functional Category

Lubricant; oleaginous vehicle.

Applications in Pharmaceutical Formulation or Technology

Canola oil is a refined rapeseed oil obtained from particular species of rapeseed that have been genetically selected for their low erucic acid content.(4) In pharmaceutical formulations, canola oil is used mainly in topical preparations such as soft soaps and liniments. It is also used in cosmetics.

Description

A clear, light yellow-colored oily liquid with a bland taste.

Pharmacopeial Specifications

—

Typical Properties

Acid value: 40.5

Density: 0.913–0.917 g/cm3

Erucic acid: 42.0%

Flash point: 290–3308C

Free fatty acid: 40.05% as oleic acid

Freezing point: —10 to —28C

Iodine number: 94–126

Refractive index: n40 = 1.465–1.469

Saponification value: 186–198

Solubility: soluble in chloroform and ether; practically in- soluble in ethanol (95%); miscible with fixed oils.

Viscosity (dynamic): 77.3–78.3 mPa s (77.3–78.3 cP) at 208C

Stability and Storage Conditions

Canola oil is stable and should be stored in an airtight, light- resistant container in a cool, dry place. During storage, grassy, paintlike, or rancid off-flavors can develop.

Flavor deterioration has been attributed mainly to second- ary oxidation products of linolenic acid, which normally makes up 9–15% of the fatty acids in canola oil. Storage tests of canola oil showed sensory changes after 2–4 days at 60–658C in comparison to 16 weeks at room temperature. Canola oil seems to be more stable to storage in light than cottonseed oil and soybean oils, but is less stable than sunflower oil.(5) In addition, the effects of various factors on sediment formation in canola oil have been reported.(6)

It has been reported that oils stored at 28C showed the highest rate of sediment formation, followed by those stored at 68C.(5) All samples showed little sediment formation, as measured by turbidity, during storage at 128C. Removal of sediment from canola oil prior to storage by cold precipitation and filtration did not eliminate this phenomenon, which still developed rapidly at 28C.

A study on the effect of heating on the oxidation of low linolenic acid canola oil at frying temperatures under nitrogen and air clearly showed that a significantly lower development of oxidation was evident for the low linolenic acid canola oil. Reduction in the linolenic acid content of canola oil reduced the development of room odor at frying temperatures.

Canola Oil 109

Incompatibilities

—

Method of Manufacture

Canola oil is obtained by mechanical expression or n-hexane extraction from the seeds of Brassica napus (Brassica campes- tris) var. oleifera and certain other species of Brassica (Cruciferae). The crude oil thus obtained is refined, bleached, and deodorized to substantially remove free fatty acids, phospholipids, color, odor and flavor components, and miscellaneous nonoil materials.

Safety

Canola oil is generally regarded as an essentially nontoxic and nonirritant material and has been accepted by the FDA for use in cosmetics, foods, and pharmaceuticals.

Rapeseed oil has been used for a number of years in food applications as a cheap alternative to olive oil. However, there are large amounts of erucic acid and glucosinolates in conventional rapeseed oil, both substances being toxic to humans and animals.(7) Canola oil derived from genetically selected rapeseed plants that are low in erucic acid content has been developed to overcome this problem.

Feeding studies in rats have suggested that canola oil is nontoxic to the heart, although it has also been suggested that the toxicological data may be unclear.(8)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Spillages of this material are very slippery and should be covered with an inert absorbent material prior to disposal. Canola oil poses a slight fire hazard.

Regulatory Status

Accepted for use by the FDA in cosmetics and foods. Included in the FDA Inactive Ingredients Guide (oral capsules). Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Almond oil; corn oil; cottonseed oil; peanut oil; rapeseed oil; sesame oil; soybean oil.

Rapeseed oil

CAS number: [8002-13-9]

Synonyms: Calchem H-102; colza oil; rape oil.

Appearance: a clear, yellow to dark yellow-colored oily liquid.

Iodine number: 94–120

Peroxide value: <5

Saponification value: 168–181

Comments: rapeseed oil contains 40–55% erucic acid. It is an edible oil and has been primarily used as an alternative, in foods and some pharmaceutical applications, to the more expensive olive oil. However, the safety of rapeseed oil as part of the diet has been questioned; see Section 14.

Comments

Canola oil has the lowest level of saturated fat compared to all other oils on the market at present. It has both a high protein (28%) and a high oil content (40%). When the oil is extracted,

a high-quality and highly palatable feed concentrate of 37% protein remains. Canola oil is also high in the monounsaturated fatty acid oleic acid; see Table III.

The content of tocopherol, a natural antioxidant in canola, is comparable to those of peanut and palm oil. This is an important factor for oils with high linolenic acid content, which can reduce the shelf-life of the product, while the natural antioxidant, if present, can prevent oxidation during storage and processing.

Suggested specifications for refined, bleached, and deodor- ized canola oil are shown in Table IV. A specification for canola oil is contained in the Food Chemicals Codex (FCC).

The EINECS number for canola oil is 232-313-5.

Table III: Comparison of the composition of crude soybean, canola, palm, and peanut oils.

Components Canola Palm Peanut Soybean

Fatty acid (%) 0.4–1.0 4.6 0.5–1.0 0.3–0.7

Phosphatides (gum) 3.6 0.05–0.1 0.3–0.4 1.2–1.5

(%)

Sterols/triterpene 0.53 0.1–0.5 0.2 0.33

alcohol (%)

Tocopherols (%) 0.06 0.003–0.1 0.02–0.06 0.15–0.21

Carotenoids (mg/kg) 25–50 500–1600 >1 40–50

Chlorophyll/ 5–25 — — 1–2

pheophytins (ppm)

Sulfur (ppm) — — — 12–17

Iodine value 112–131 44–60 84–100 123–139

Table IV: Suggested specifications for canola oil.

Test Minimum Maximum

Acid value — 6

Iodine value 110 126

Heavy metal (as lead) — 5 mg/kg

Refractive index n40 1.465 1.467

Free fatty acid (as oleic) — 0.05%

Erucic acid — 2%

Moisture and impurities — 0.05%

Saponification value (mg KOH/g oil) 182 193

Unsaponifiable matter — 15 g/kg

Specific References

Devinat G, Biasini S, Naudet M. Sulfur-compounds in the rapeseed oils. Rev Fr Corps Gras 1980; 27: 229–236.

Wijesundera RC, Ackman RG. Evidence for the probable presence of sulfur-containing fatty-acids as minor constituents in canola oil. J Am Oil Chem Soc 1988; 65: 959–963.

Abraham V, de Man JM. Determination of total sulfur in canola oil. J Am Oil Chem Soc 1987; 64: 384–387.

Hiltunen R, Huhtikangas A, Hovinen S. Breeding of a zero erucic spring turnip-rape cultivar, Brassica campestris L. adapted to Finnish climatic conditions. Acta Pharm Fenn 1979; 88: 31–34.

Przybylski R, Billiaderis CG, Eskin NAM. Formation and partial characterization of canola. J Am Oil Chem Soc 1993; 70: 1009– 1016.

Liu H, Billiaderis CG, Przybylski R. Effects of crystalization conditions on sediment. J Am Oil Chem Soc 1994; 71: 409–418.

110 Canola Oil

Anonymous. Rapeseed oil revisited. Lancet 1974; ii: 1359–1360.

Anonymous. Rapeseed oil and the heart. Lancet 1973; ii: 193.

General References

Koseoglu SS, Iusas EW. Recent advances in canola oil hydrogenations. J Am Oil Chem Soc 1990; 67: 3947.

Malcolmson LJ, Vaisey-Genser M, Przybylski R, Eskin NAM. Sensory stability of canola oil: present status. J Am Oil Chem Soc 1994; 71: 435–440.

BP: Carbomers PhEur: Carbomera USPNF: Carbomer

Note that the USPNF 23 contains several individual carbomer monographs; see Sections 4 and 9.

Synonyms

Acritamer; acrylic acid polymer; Carbopol; carboxy poly- methylene, polyacrylic acid; carboxyvinyl polymer; Pemulen; Ultrez.

Chemical Name and CAS Registry Number

Carbomer [9003-01-4]

Note that carbomer 910, 934, 934P, 940, 941, 971P and 974P resins share the common CAS registry number 9003-01-

4. Carbomer 1342 is a copolymer and has a different CAS registry number.

Empirical Formula and Molecular Weight

Carbomers are synthetic high-molecular-weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol. They contain between 56% and 68% of carboxylic acid (COOH) groups calculated on the dry basis. The BP 2004 and PhEur 2005 have a single monograph describing carbomer; the USPNF 23 contains several mono- graphs describing individual carbomer grades that vary in aqueous viscosity and in labeling for oral or non-oral use. The molecular weight of carbomer resins is theoretically estimated at 7 × 105 to 4 × 109. In an effort to measure the molecular weight between crosslinks, MC, researchers have extended the network theory of elasticity to swollen gels and have utilized the inverse relationship between the elastic modulus and MC.(1–3) Estimated MC values of 237 600 g/mol for Carbopol 941 and of

Carbomer polymers are formed from repeating units of acrylic acid. The monomer unit is shown above. The polymer chains are crosslinked with allyl sucrose or allyl pentaerythritol. See also Section 4.

Functional Category

Bioadhesive; emulsifying agent; release-modifying agent; sus- pending agent; tablet binder; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Carbomers are mainly used in liquid or semisolid pharmaceu- tical formulations as suspending or viscosity-increasing agents. Formulations include creams, gels, and ointments for use in ophthalmic,(5–7) rectal,(8–10) and topical preparations.(11–17) Carbomer grades, even with a low residual benzene content, such as carbomer 934P, are no longer included in the PhEur 2005. However, carbomer having low residuals only of other solvents than the ICH-defined ‘Class I OVI solvents’ may be used in Europe. Carbomer having low residuals only of ethyl acetate, such as carbomer 971P or 974P, may be used in oral preparations, in suspensions, tablets, or sustained release tablet formulations.(18–22) In tablet formulations, carbomers are used as dry or wet binders and as a rate controlling excipient. In wet granulation processes, water or an alcohol–water blend is used as the granulating fluid. Anhydrous organic solvents have also been used, with the inclusion of a polymeric binder. The tackiness of the wet mass can be reduced with the addition of certain cationic species to the granulating fluid(23) or, in the case of water, with talc in the formulation. Carbomer resins have also been investigated in the preparation of sustained-release matrix beads,(23) as enzyme inhibitors of intestinal proteases in peptide-containing dosage forms,(24,25) as a bioadhesive for a cervical patch(26) and for intranasally administered micro-

(27)

104 400 g/mol for Carbopol 940 have been reported.(4) In general, carbomer resins with lower viscosity and lower rigidity will have higher MC values. Conversely, higher-viscosity, more rigid carbomer resins will have lower MC values.

Structural Formula

spheres, in magnetic granules for site-specific drug delivery to the esophagus(28) and in oral mucoadhesive controlled drug delivery systems.(29,30) Carbomers are also employed as emulsifying agents in the preparation of oil-in-water emulsions for external use. For this purpose, the carbomer is neutralized partly with sodium hydroxide and partly with a long-chain amine such as stearylamine. Carbomer 951 has been investi- gated as a viscosity-increasing aid in the preparation of multiple emulsion microspheres.(31) Carbomers are also used in cos- metics. Therapeutically, carbomer gel formulations have proved efficacious in improving symptoms of moderate-to- severe dry eye syndrome.(32,33) See Table I.

Table I: Uses of carbomers.

Use Concentration (%)

Emulsifying agent 0.1–0.5

Gelling agent 0.5–2.0

Suspending agent 0.5–1.0

Tablet binder 5.0–10.0

112 Carbomer

SEM: 1

Excipient: Carbomer 971P (Carbopol 971P) Manufacturer: BF Goodrich

Magnification: 2000×

Voltage: 25 kV

Description

Carbomers are white-colored, ‘fluffy’, acidic, hygroscopic powders with a slight characteristic odor.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for carbomers.

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Aqueous viscosity (mPa s) 300–115 000 —

Carbomer 934 (0.5% w/v) — 30 500–39 400

Carbomer 934P (0.5% w/v) — 29 400–39 400

Carbomer 940 (0.5 w/v) — 40 000–60 000(a)

Carbomer 941 (0.5 w/v) — 4 000–11 000

Carbomer 1342 (1.0% w/v) — 9 500–26 500

Loss on drying 43.0% 42.0%

Sulfated ash 44.0% —

Heavy metals 420 ppm 40.002%

Benzene 42 ppm —

Carbomer 910 — 40.5%

Carbomer 934 — 40.5%

Carbomer 934P — 40.01%

Carbomer 940 — 40.5%

Carbomer 941 — 40.5%

Carbomer 1342 — 40.2%

Free acrylic acid 40.25% —

Organic volatile impurities — +

Assay (COOH content) 56.0–68.0% 56.0–68.0%

(a) See USPNF 23 Suppl. 1.0 for new method.

Note that the USPNF 23 has several monographs for different carbomer grades, while the BP 2004 and the PhEur 2005 have only a single monograph. Other grades of carbomer

SEM: 2

Excipient: Carbomer 971P (Carbopol 971P) Manufacturer: BF Goodrich

Magnification: 6000×

Voltage: 25 kV

meet the existing USPNF 23 standards as indicated above. Carbomer 974P is covered by the monograph for carbomer 934P in the USPNF 23. Likewise, carbomer 980 meets the specifications for carbomer 940; carbomers 971P and 981 meet the monograph limits for carbomer 941. Carbomer resins are also covered either individually or together in other pharma- copeias. Unless otherwise indicated, the test limits shown above apply to all grades of carbomer.

Typical Properties

Acidity/alkalinity:

pH = 2.7–3.5 for a 0.5% w/v aqueous dispersion; pH = 2.5–3.0 for a 1% w/v aqueous dispersion.

Density (bulk): 1.76–2.08 g/cm3

Density (tapped): 1.4 g/cm3

Glass transition temperature: 100–1058C

Melting point: decomposition occurs within 30 minutes at 2608C. See Section 11.

Moisture content: normal water content is up to 2% w/w. However, carbomers are hygroscopic and a typical equili- brium moisture content at 258C and 50% relative humidity is 8–10% w/w. The moisture content of a carbomer does not affect its thickening efficiency, but an increase in the moisture content makes the carbomer more difficult to handle because it is less readily dispersed.

Particle size distribution: primary particles average about

0.2 mm in diameter. The flocculated powder particles average 2–7 mm in diameter and cannot be broken down into the primary particles. Recently, a granular carbomer having a particle size in the range 180–425 mm has been introduced. Its bulk and tap densities are also higher than those of other carbomers.

Solubility: soluble in water and, after neutralization, in ethanol (95%) and glycerin.

Although they are described as ‘soluble’, carbomers do not dissolve but merely swell to a remarkable extent, since they are three-dimensionally crosslinked microgels. Further- more, the pharmacopeial specifications are unclear, in that neutralization with long-chain aliphatic amines or ethoxy-

Carbomer 113

lated long-chain amines is required for swellability in ethanol, and with water-soluble amines for swellability in glycerin.

Specific gravity: 1.41

Viscosity (dynamic): carbomers disperse in water to form acidic colloidal dispersions of low viscosity that, when neutralized, produce highly viscous gels. Carbomer powders should first be dispersed into vigorously stirred water, taking care to avoid the formation of indispersible lumps, then neutralized by the addition of a base. The Carbopol ETD and Ultrez 10 series of carbomers was introduced to overcome some of the problems of dispersing the powder into aqueous solvents. These carbomer resins wet quickly yet hydrate slowly, while possessing a lower unneutralized dispersion viscosity. Agents that may be used to neutralize carbomer polymers include amino acids, borax, potassium hydroxide, sodium bicarbonate, sodium hydroxide, and polar organic amines such as triethanolamine. Lauryl and stearyl amines may be used as gelling agents in nonpolar systems. One gram of carbomer is neutralized by approximately 0.4 g of sodium hydroxide. During preparation of the gel, the solution should be agitated slowly with a broad, paddlelike stirrer to avoid introducing air bubbles. Neutralized aqueous gels are more viscous at pH 6–11. The viscosity is considerably reduced at pH values less than 3 or greater than 12 or in the presence of strong electrolytes.(23,34) Gels rapidly lose viscosity on exposure to ultraviolet light, but this can be minimized by the addition of a suitable antioxidant. See also Section 11.

Stability and Storage Conditions

Carbomers are stable, hygroscopic materials that may be heated at temperatures below 1048C for up to 2 hours without affecting their thickening efficiency. However, exposure to excessive temperatures can result in discoloration and reduced stability. Complete decomposition occurs with heating for 30 minutes at 2608C. Dry powder forms of carbomer do not support the growth of molds and fungi. In contrast, micro- organisms grow well in unpreserved aqueous dispersions and therefore an antimicrobial preservative such as 0.1% w/v chlorocresol, 0.18% w/v methylparaben–0.02% w/v propyl- paraben, or 0.1% w/v thimerosal should be added. The addition of certain antimicrobials, such as benzalkonium chloride or sodium benzoate, in high concentrations (0.1% w/v) can cause cloudiness and a reduction in viscosity of carbomer dispersions. Aqueous gels may be sterilized by autoclaving(7) with minimal changes in viscosity or pH, provided care is taken to exclude oxygen from the system, or by gamma irradiation, although this technique may increase the viscosity of the formulation.(35,36) At room temperature, carbomer dispersions maintain their viscosity during storage for prolonged periods. Similarly, dispersion viscosity is main- tained, or only slightly reduced, at elevated storage tempera- tures if an antioxidant is included in the formulation or if the dispersion is stored protected from light. Exposure to light causes oxidation that is reflected in a decrease in dispersion viscosity. Stability to light may be improved by the addition of 0.05–0.1% w/v of a water-soluble UV absorber such as benzophenone-2 or benzophenone-4 in combination with 0.05–0.1% w/v edetic acid. The UV stability of carbomer gels may also be improved by using triethanolamine as the neutralizing base; see Section 10.

Carbomer powder should be stored in an airtight, corro- sion-resistant container in a cool, dry place. The use of glass, plastic, or resin-lined containers is recommended for the

storage of formulations containing carbomer. Packaging in aluminum tubes usually requires the formulation to have a pH less than 6.5, and packaging in other metallic tubes or containers necessitates a pH greater than 7.7 to prolong carbomer stability.

Incompatibilities

Carbomers are discolored by resorcinol and are incompatible with phenol, cationic polymers, strong acids, and high levels of electrolytes. Certain antimicrobial adjuvants should also be avoided or used at low levels, see Section 11. Trace levels of iron and other transition metals can catalytically degrade carbomer dispersions. Intense heat may be generated if a carbomer is in contact with a strong basic material such as ammonia, potassium or sodium hydroxide, or strongly basic amines.

Certain amino-functional actives form water-insoluble complexes with carbomer; often this can be prevented by adjusting the solubility parameter of the fluid phase using appropriate alcohols and polyols.

Carbomers also form pH-dependent complexes with certain polymeric excipients. Adjustment of solubility parameter can also work in this situation.

Method of Manufacture

Carbomers are synthetic, high-molecular-weight, crosslinked polymers of acrylic acid. These poly(acrylic acid) polymers are crosslinked with allyl sucrose or allyl pentaerythritol. The polymerization solvent used most commonly was benzene; however, some of the newer commercially available grades of carbomer are manufactured using either ethyl acetate or a cyclohexane–ethyl acetate cosolvent mixture. The Carbopol ETD resins are produced in the cosolvent mixture with a proprietary polymerization aid, and these resins are crosslinked with a polyalkenyl polyether.

Safety

Carbomers are used extensively in nonparenteral products, particularly topical liquid and semisolid preparations. They may also be used in oral formulations, although only certain grades can be used; see Section 18. Acute oral toxicity studies in animals indicate that carbomer 934P has a low oral toxicity, with doses up to 8 g/kg being administered to dogs without fatalities occurring. Carbomers are generally regarded as essentially nontoxic and nonirritant materials; there is no evidence in humans of hypersensitivity reactions to carbomers used topically. In humans, oral doses of 1–3 g of carbomer have been used as a bulk laxative.

LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934(37) LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934P LD50 (guinea pig, oral): 2.5 g/kg for carbomer 940 LD50 (mouse, IP): 0.04 g/kg for carbomer 934P

LD50 (mouse, IP): 0.04 g/kg for carbomer 940 LD50 (mouse, IV): 0.07 g/kg for carbomer 934P LD50 (mouse, IV): 0.07 g/kg for carbomer 940 LD50 (mouse, oral): 4.6 g/kg for carbomer 934P LD50 (mouse, oral): 4.6 g/kg for carbomer 934 LD50 (mouse, oral): 4.6 g/kg for carbomer 940 LD50 (rat, oral): 10.25 g/kg for carbomer 910 LD50 (rat, oral): 2.5 g/kg for carbomer 934P LD50 (rat, oral): 4.1 g/kg for carbomer 934

LD50 (rat, oral): 2.5 g/kg for carbomer 940 LD50 (rat, oral): > 1g/kg for carbomer 941

114 Carbomer

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Excessive dust generation should be minimized to avoid the risk of explosion (lowest explosive concentration is 100 g/m3). Carbomer dust is irritat- ing to the eyes, mucous membranes, and respiratory tract. In contact with the eye, carbomer dust is difficult to remove with water owing to the gelatinous film that forms; saline should therefore be used for irrigation purposes. Gloves, eye protec- tion, and a dust respirator are recommended during handling.

Regulatory Acceptance

Included in the FDA Inactive Ingredients Guide (oral suspen- sions, tablets; ophthalmic, rectal, and topical preparations transdermal preparations, vaginal suppositories). Included in nonparenteral medicines licensed in Europe. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Polycarbophil.

med 11

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